Diet-induced obesity results in endothelial cell desensitization to VEGF-A and permanent islet vascular dysfunction

Background Pancreatic islet microvasculature is essential for optimal islet function and glucose homeostasis. However, islet vessel pathogenesis and its role in the manifestation of metabolic disorders remain understudied. Here we depict a time-resolved decline of intra-islet endothelial cell sensitivity to vascular endothelial cell growth factor A (VEGF-A) in a mouse model of diet-induced obesity. Methods Mice were transplanted with reporter islets in their eyes and put on different diet schemes for 48 weeks. Islet vascular morphology, VEGF-A signaling activity in islet endothelial cells and vessel function were longitudinally monitored by in vivo imaging, while the metabolic implication of islet vessel alterations was measured by glucose tolerance tests and insulin secretion assays. Results In parallel with substantial islet vasculature remodeling, diminished VEGF-A response in islet endothelial cells emerged after 12 weeks of western diet feeding. This led to vessel barrier dysfunction and hemodynamic dysregulation, which delayed transportation of secreted insulin into the blood. Islet vessels also exhibited a remarkable metabolic memory long after the removal of western diet. Neither islet endothelial cell VEGF-A sensitivity nor the vascular damage elicited by 24 weeks of western diet feeding was restored by switching to control diet for another 24 weeks. As a result, these refed mice still exhibited mild but significant impairment in glucose clearance, despite a complete normalization of body weight and insulin sensitivity. While plasma levels of soluble VEGF receptor 1 – the natural VEGF-A trap – were similar in all diet groups, increased activity of atypical protein kinase C (aPKC) was observed under both western diet and recovery conditions, which inhibited VEGF receptor 2 (VEGFR2) internalization and dampened VEGF-A triggered signal transduction in vivo and in human endothelial cells cultured under diet-mimicking conditions. Conclusions Long-term western diet feeding causes irreversible VEGF-A desensitization in islet endothelial cells and islet vessel dysfunction which undermines glucose homeostasis.